The National Institute of Allergy and Infectious Diseases has awarded the Perelman School of Medicine at the University of Pennsylvania a five-year, $10 million renewal of a program project to study the oldest part of the human immune system called the complement system, or simply “complement.” Complement is a network of more than 50 proteins in the blood and on cell surfaces and is part of the innate immune system, in contrast to the adaptive system consisting of antibodies which can “learn” and adapt themselves on the fly to different antigens. The complement proteins quietly cruise the blood system, keeping a low profile until triggered into action.

John Lambris, the Ralph and Sallie Weaver Professor of Research Medicine in the department of pathology and laboratory medicine, has been studying the complement system for many years and is the lead investigator on the renewed program project. Complement has been shown to contribute to a broad spectrum of immune, inflammatory and age-related diseases. Dr. Lambris and colleagues are developing novel therapeutics to tame inappropriate complement activation and protect cell surfaces from an attack by this defense system.

Using small inhibitors of central complement components, engineered regulatory proteins and protective cell coatings, they are demonstrating the benefit of therapeutic complement modulation in a variety of clinical situations, including organ transplantation, hemodialysis-related complications and periodontitis. The latter disease is being investigated in collaboration with the Penn School of Dental Medicine, under the project leadership of George Hajishengallis. Although individual diseases have distinct triggers of complement activation, it is likely that there are common patterns of downstream immunomodulatory mechanisms that will broaden our perception of complement’s pathophysiological role and guide the development of complement therapeutics.

During the initial five years of the program project, the team unraveled several new mechanisms of complement and demonstrated surprising roles of this ancient system in cancer and liver regeneration. At the same time, the project produced an impressive arsenal of complement modulators, some of which already showed clinical.

“Although the value of inhibiting complement therapeutically has long been recognized, the availability of complement-directed drugs in the clinic is still very limited,” said Dr. Lambris. The development and evaluation of a toolbox of complement inhibitors that block the system at various functional key steps will therefore be a centerpiece of the renewal.

“We have known about complement for over 100 years, it continues to surprise us, with discoveries of new functions that reach beyond microbial defense to include roles in immune surveillance, homeostasis and development,” said Dr. Lambris. “What’s more, it is becoming evident that these functions rely on crosstalk with other bodily systems. However, complement-related diseases have often been studied in an isolated manner and without considering crosstalk.”